Extracellular beta-amyloid (AP) deposition and intracellular neurofibrillary tangles (NFTs) are two hallmark lesions of Alzheimer's disease. Abeta derives from amyloid precursor protein (APP) through a series of proteolytic cleavage; and NFTs are bundles of hyperphosphorylated microtubule-associated protein tau that are self-assembled into paired helical filaments. Study of the correlations between APP/Abeta and tauopathy would greatly facilitate our understanding of AD pathology. In this proposal, cellular and molecular approaches will be employed to study the underlying mechanisms correlating APP/Ap and tauopathy, using CDK5 kinase as a candidate. The proposed study has four specific aims: 1. Determine whether the inhibition of eye I In-dependent kinase 5 (CDK5) activity/activation by APP results in reduced tau phosphorylation and aggregation. 2. Determine which molecular domains of APP/APLP are necessary for regulation of tau kinase activation. 3. Determine the mechanism underlying activation of CDK5 by reducing APP levels. 4. Determine the physiological roles of APP in tau kinase activation and tauopathy in transgenic mouse models. Alzheimer's disease is the most common form of dementia in the elderly population. The proposed study offers a comprehensive view of AD by integrating Ap, NFTs and neuronal loss, the principal pathologic entities of AD.